Amphotericin B (Conventional)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous, as desoxycholate [preservative free]:

Generic: 50 mg (1 ea)

Pharmacology

Mechanism of Action

Binds to ergosterol altering cell membrane permeability in susceptible fungi and causing leakage of cell components with subsequent cell death. Proposed mechanism suggests that amphotericin causes an oxidation-dependent stimulation of macrophages (Lyman 1992).

Pharmacokinetics/Pharmacodynamics

Absorption

Poor oral absorption

Distribution

Minimal amounts enter the aqueous humor, bile, pericardial fluid, pleural fluid, and synovial fluid

CNS penetration:

Preterm neonates (GA: 27.4 ± 5 weeks): High interpatient variability; 40% to 90% of serum concentrations (Baley 1990)

Adults: Poor (inflamed or noninflamed meninges)

Excretion

Urine (2% to 5% as biologically active form); ~40% eliminated over a 7-day period and may be detected in urine for at least 7 weeks after discontinued use

Clearance (Benson 1989):

Infants and Children (8 months to 9 years): 0.57 ± 0.152 mL/minute/kg

Children and Adolescents (10-14 years): 0.24 ± 0.02 mL/minute/kg

Time to Peak

Within 1 hour following a 4- to 6-hour dose

Half-Life Elimination

Premature neonates (GA: 27.4 ± 5 weeks): 14.8 hours (range: 5 to 82 hours) (Baley 1990)

Infants and Children (4 months to 14 years): 18.1 ± 6.6 hours (range: 11.9 to 40.3 hours) (Benson 1989)

Adults: Biphasic: Initial: 15 to 48 hours; Terminal: 15 days

Protein Binding

Plasma: 90%

Use: Labeled Indications

Life-threatening fungal infections: Treatment of patients with progressive, potentially life-threatening fungal infections: Aspergillosis, cryptococcosis (torulosis), North American blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, zygomycosis (including mucormycosis due to susceptible species of the genera Absidia, Mucor, and Rhizopus), and infections due to related susceptible species of Conidiobolus, Basidiobolus, and sporotrichosis.

Leishmaniasis: Alternative treatment in patients with American (New World) mucocutaneous leishmaniasis

Use: Off Label

Candidiasis, endophthalmitis (intravitreal)yes

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, intravitreal administration of amphotericin B (conventional) (extemporaneously compounded) is an effective and recommended adjunct to systemic antifungal agents in patients with candida chorioretinitis with macular involvement (with or without vitritis).

Candidiasis, esophageal (non-HIV-infected patients)yes

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, amphotericin B (conventional) is an effective and recommended alternative treatment option for esophageal candidiasis in patients who cannot tolerate oral therapy.

Candidiasis, esophageal, in HIV-infected patientsyes

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, amphotericin B (conventional) is an effective and recommended alternative agent for the treatment of esophageal candidiasis in adolescent and adult HIV-infected patients.

Candidiasis, oropharyngeal (fluconazole-refractory) (oral)yes

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, amphotericin B (conventional) oral suspension (extemporaneously compounded) is an effective and recommended treatment option for fluconazole-refractory oropharyngeal candidiasis.

Candidiasis, urinary tractyes

Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, bladder irrigation with amphotericin B (conventional) is effective and recommended for a variety of urinary tract candidiasis infections, including symptomatic cystitis, pyelonephritis, fungus balls, and for asymptomatic candiduria in patients undergoing urologic procedures. In the treatment of fungus balls, irrigation via nephrostomy tubes using an extemporaneously prepared amphotericin B (conventional) solution is recommended. In the treatment of symptomatic cystitis due to fluconazole-resistant species (eg, C. krusei, C. glabrata), bladder irrigation of an extemporaneously prepared amphotericin B (conventional) solution is recommended.

Leishmaniasis, visceralyes

Based on the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) clinical practice guidelines for the diagnosis and treatment of leishmaniasis and the HHS guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents, amphotericin B (conventional) is a recommended alternative agent for the management of visceral leishmaniasis.

Ocular aspergillosis (ophthalmic)cyes

Although topical administration of amphotericin B drops may be adequate in cases of aspergillus keratitis, more advanced ophthalmic infections may require more invasive techniques for delivering the drug to the deeper layers of the eye. Some debate exists among ophthalmologists about whether amphotericin B should be administered into the vitreous humor (intravitreal injection) or into the aqueous humor (intracameral injection), for the treatment of aspergillus endophthalmitis. IDSA guidelines recommend intravitreal injection for endophthalmitis and intracameral injection for refractory keratitis that does not respond to topical therapy.

Contraindications

Hypersensitivity to amphotericin or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: Conventional amphotericin formulations (desoxycholate [Amphocin, Fungizone]) may be confused with lipid-based formulations (AmBisome, Abelcet, Amphotec). Lipid-based and conventional formulations are not interchangeable and have different dosage recommendations. Overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products.

Note: Premedication: For patients who experience infusion-related immediate reactions, premedicate with the following drugs 30 to 60 minutes prior to drug administration: NSAID and/or diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone. If the patient experiences rigors during the infusion, meperidine may be administered.

Test dose: IV: 1 mg infused over 20 to 30 minutes. Many clinicians believe a test dose is unnecessary.

Susceptible fungal infections: IV: Adults: 0.3 to 1.5 mg/kg/day; 1 to 1.5 mg/kg over 4 to 6 hours every other day may be given once therapy is established; aspergillosis, rhinocerebral mucormycosis, often require 1 to 1.5 mg/kg/day; do not exceed 1.5 mg/kg/day

Aspergillosis, disseminated: IV: 0.6 to 0.7 mg/kg/day for 3 to 6 months. Note: IDSA recommends amphotericin B (conventional) be reserved for use in resource limited settings when no alternatives are available; voriconazole is preferred therapy for invasive Aspergillus infections (IDSA [Patterson 2016]).

Aspergillosis (ocular) (off-label use): Ophthalmic:

Intraocular: Inject 5 to 10 mcg in a 0.1 mL volume as a single dose intravitreally or intracamerally to the affected eye; may be repeated in 4 to 7 days as clinically indicated (Kaushik 2001; Patterson 2016). Guidelines recommend concomitant vitrectomy and use in combination with systemic voriconazole (Patterson 2016).

Topical (0.1% to 0.2% solution): Apply to affected eye every 30 to 60 minutes until symptoms resolve (may take weeks) (Kaushik 2001; Ritterband 2002; Tamcelik 2002). Note: Ophthalmic natamycin is the preferred treatment (Patterson 2016)

Blastomycosis: Moderately severe to severe pulmonary disease, disseminated extrapulmonary disease or immunosuppressed patients: IV: 0.7 to 1 mg/kg/day for 1 to 2 weeks or until improvement is noted, followed by oral itraconazole for 6 to 12 months (IDSA [Chapman 2008])

Candidiasis:

CNS infection (failed to respond to systemic therapy and device removal or when ventricular device cannot be removed) (off-label): Intraventricular: 0.01 to 0.5 mg/2 mL of an extemporaneously prepared solution in D5W administered through the device into the ventricle (IDSA [Pappas 2016]; IDSA [Tunkel 2017])

Endophthalmitis due to Candida (off-label use): Patients with vitritis or with macular involvement (with or without vitritis): Intravitreal: 5 to 10 mcg/0.1 mL of an extemporaneously prepared solution in sterile water; administer with concomitant systemic antifungal therapy (IDSA [Pappas 2016])

Esophageal:

Non-HIV-infected patients (alternative therapy) (off-label use): IV: 0.3 to 0.7 mg/kg/day. Consider step down to an oral antifungal once patient is able to tolerate oral intake. In fluconazole-refractory disease, continue amphotericin B (conventional) for 21 days (IDSA [Pappas 2016])

HIV-infected patients (alternative therapy) (off-label use): IV: 0.6 mg/kg/day for 14 to 21 days (HHS [OI adult 2017])

Invasive candidiasis (alternative therapy): IV: 0.5 to 0.7 mg/kg/day; dose may be increased to as high as 1 mg/kg/day for infections caused by C. glabrata or C. krusei. Note: Given poor tolerability (eg, nephrotoxicity, infusion-related toxicity), experts preferentially recommend lipid formulations when available (IDSA [Pappas 2016]).

Oropharyngeal (fluconazole-refractory): Non-HIV-infected patients (alternative therapy) (off-label use): Oral: 100 mg of an extemporaneously compounded 100 mg/mL suspension 4 times daily (IDSA [Pappas 2016])

Urinary tract candidiasis (off-label use) (IDSA [Pappas 2016]):

Asymptomatic candiduria in patients undergoing urologic procedures: IV: 0.3 to 0.6 mg/kg daily for several days before and after the procedure

Fungus balls: Irrigation via nephrostomy tubes (off-label route): Irrigate with an extemporaneously prepared solution of 25 to 50 mg in 200 to 500 mL sterile water (final concentration range: 0.05 to 0.25 mg/mL)

Pyelonephritis: C. krusei or fluconazole-resistant C. glabrata: IV: 0.3 to 0.6 mg/kg/day for 1 to 7 days (with or without flucytosine for fluconazole-resistant C. glabrata)

Symptomatic cystitis:

C. krusei or fluconazole-resistant C. glabrata: IV: 0.3 to 0.6 mg/kg/day for 1 to 7 days

Fluconazole-resistant species (eg. C. krusei, C. glabrata) Bladder irrigation (off-label route): Irrigate with a 0.05 mg/mL (50 mg/L) sterile water solution instilled for 5 to 7 days or until cultures are clear. Note: Recommended for use in conjunction with other treatment modalities (Fisher 2011).

Coccidioidomycosis in HIV-infected patients with severe, non-meningeal infection (ie, diffuse pulmonary or severely ill with extrathoracic disseminated disease): IV: 0.7 to 1 mg/kg/day until clinical improvement, then initiate triazole therapy (eg, fluconazole or itraconazole) (HHS [OI adult 2017])

Cryptococcal disease, HIV-infected patients:

Disseminated (non-CNS disease) or severe pulmonary disease: Induction: 0.7 to 1 mg/kg/day (with flucytosine [preferred] or fluconazole or without a concomitant agent) for 2 weeks, then change to oral fluconazole for consolidation/maintenance therapy (HHS [OI adult] 2017)

Meningitis: IV: Induction: 0.7 to 1 mg/kg/day (with flucytosine [preferred] or fluconazole or without a concomitant agent) for 2 weeks, then change to oral fluconazole for consolidation/maintenance therapy (HHS [OI adult] 2017)

Histoplasmosis: Moderately severe to severe pulmonary or disseminated disease (off-label): IV: 0.7 to 1 mg/kg/day for 1 to 2 weeks, followed by oral itraconazole for 12 weeks (pulmonary disease) or 12 months (disseminated disease) (IDSA [Wheat 2007])

Leishmaniasis (alternative agent):

Cutaneous: IV: 0.5 to 1 mg/kg/dose once daily or every other day for a total cumulative dose of ~15 to 30 mg/kg (IDSA/ASTMH [Aronson 2016])

Mucosal: IV: 0.5 to 1 mg/kg/dose once daily or every other day for a total cumulative dose of ~20 to 45 mg/kg (IDSA/ASTMH [Aronson 2016])

Visceral (off-label): IV: 1 mg/kg/dose once daily or every other day for a total cumulative dose of 15 to 20 mg/kg (IDSA/ASTMH [Aronson 2016])

Visceral, HIV-infected (off-label): IV: 0.5 to 1 mg/kg/dose once daily for a total cumulative dose of 1,500 to 2,000 mg (HHS [OI adult 2017])

Sporotrichosis: Pulmonary, meningeal, osteoarticular, or disseminated (off-label): IV: 0.7 to 1 mg/kg/day; after the patient has shown a favorable response, can change to oral itraconazole for suppressive therapy for a total duration of therapy of ≥12 months (IDSA [Kauffman 2007)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Medication errors, including deaths, have resulted from confusion between lipid-based forms of amphotericin (Abelcet, Amphotec, AmBisome) and conventional amphotericin B for injection; conventional amphotericin B for injection doses should not exceed 1.5 mg/kg/day

Note: Premedication: For patients who experience infusion-related immediate reactions, premedicate with the following drugs 30 to 60 minutes prior to drug administration: NSAID (with or without diphenhydramine) or acetaminophen with diphenhydramine or hydrocortisone. If the patient experiences rigors during the infusion, meperidine may be administered.

Test dose: Infants, Children, and Adolescents: IV: 0.1 mg/kg/dose to a maximum of 1 mg; infuse over 20 to 60 minutes; an alternative method to the 0.1 mg/kg test dose is to initiate therapy with 0.25 mg/kg amphotericin administered over 6 hours; frequent observation of the patient and assessment of vital signs during the first several hours of the infusion is recommended; many clinicians believe a test dose is unnecessary

General dosing, susceptible infections:

IV: Infants, Children, and Adolescents:

Initial: 0.25 to 0.5 mg/kg/dose once daily; gradually increase daily, usually in 0.25 mg/kg increments until the desired daily dose is reached (maximum daily dose: 1.5 mg/kg/day); in critically ill patients, more rapid dosage acceleration may be warranted (eg, ≥0.5 mg/kg daily dose increase); others have initiated at target dose for life-threatening infection (HHS [OI pediatric 2013])

Maintenance dose: 0.25 to 1 mg/kg/dose once daily; rapidly progressing disease may require short-term use of doses up to 1.5 mg/kg/day; once therapy has been established, amphotericin B may be administered on an every-other-day basis at 1 to 1.5 mg/kg/dose in some cases

Intrathecal, intraventricular, or intracisternal (preferably into the lateral ventricles through a cisternal Ommaya reservoir): Limited data available; dose variable: Infants, Children, and Adolescents: 0.01 to 1 mg; frequency varies widely in the literature; administration has been reported as daily, every other day and even twice weekly (Chiou 1994; IDSA [Pappas 2016]; Murphy 2000; Red Book [AAP 2015])

Irrigation, bladder: Infants, Children, and Adolescents: Limited data available: 50 mcg/mL solution, administered as either a continuous irrigation or as an intermittent irrigation 3 times daily with a dwell time of 60 to 90 minutes (Fisher 2011; Gubbins 1999); some experts have also recommended daily administration for 5 days for the treatment of cystitis due to fluconazole-resistant Candida species (C. glabrata, C. krusei) (IDSA [Pappas 2016])

Aspergillosis:

Prophylaxis, immunocompromised: Limited data available: Infants, Children, and Adolescents: Intranasal: 7 mg amphotericin B in 7 mL sterile water was placed in a De Vilbiss atomizer and the aerosolized solution was instilled intranasally to each nostril 4 times daily delivering an average of 5 mg amphotericin/day to reduce the frequency of invasive aspergillosis in neutropenic patients (Jeffery 1991)

Endocarditis: Children and Adolescents: IV: 1 mg/kg/dose once daily with or without flucytosine (AHA [Baltimore 2015])

Blastomycosis (independent of HIV status), moderately severe to severe disease: Infants, Children, and Adolescents: IV: 0.7 to 1 mg/kg/dose once daily as initial therapy for 1 to 2 weeks, followed with oral itraconazole for a total of 12 months (IDSA [Chapman 2008])

Candidiasis; treatment:

Invasive: Infants, Children, and Adolescents: IV: 0.5 to 1 mg/kg/dose once daily; duration of therapy dependent upon severity and site of infection (IDSA [Pappas 2016])

Endocarditis: Children and Adolescents: IV: 1 mg/kg/dose once daily with or without flucytosine (AHA [Baltimore 2015])

Esophageal:

Non-HIV-exposed/-positive: Infants, Children, and Adolescents: IV: 0.3 to 0.7 mg/kg/dose once daily; consider step down to an oral antifungal once patient is able to tolerate oral intake. In fluconazole-refractory disease, continue amphotericin B for 21 days (IDSA [Pappas 2016])

HIV-exposed/-positive:

Infants and Children: IV: 0.3 to 0.7 mg/kg/dose once daily (HHS [OI pediatric 2013])

Adolescents: IV: 0.6 mg/kg/dose once daily for 14 to 21 days (HHS [OI adult 2016])

Oropharyngeal, fluconazole-refractory:

Non-HIV-exposed/-positive: Infants, Children, and Adolescents: IV: 0.3 mg/kg/dose once daily (IDSA [Pappas 2016])

HIV-exposed/-positive:

Infants and Children: IV: 0.3 to 0.5 mg/kg/dose once daily (HHS [OI pediatric 2013])

Adolescent: IV: 0.6 mg/kg/dose once daily for 14 to 21 days (HHS [OI adult 2016])

Urinary tract infections (IDSA [Pappas 2016]):

Prophylaxis, urologic procedures in patients with candiduria: Infants, Children, and Adolescents: IV: 0.3 to 0.6 mg/kg/dose once daily for several days before and after procedure

Treatment:

Cystitis: Infants, Children, and Adolescents: IV:

Asymptomatic (high-risk patients): 1 mg/kg/dose once daily

Symptomatic (C. krusei or fluconazole-resistant C. glabrata): 0.3 to 0.6 mg/kg/dose once daily for 1 to 7 days

Pyelonephritis: Infants, Children, and Adolescents: IV: 0.3 to 0.6 mg/kg/dose once daily for 1 to 7 days; depending on organism, consider addition of flucytosine

Coccidioidomycosis:

Non-HIV-exposed/-positive (IDSA [Galgiani 2005]): Infants, Children, and Adolescents:

Disseminated (non-CNS) disease: IV 0.5 to 1.5 mg/kg/dose every day or every other day; with or without concomitant azole antifungal; duration determined by clinical response

CNS disease: Intrathecal: 0.1 to 1.5 mg/dose; frequency ranging from daily to weekly (with or without concomitant azole therapy); initiate at a low dose and increase until intolerance is noted (eg, severe vomiting, exhaustion, or transient dose-related mental status changes); duration determined by clinical response

Pulmonary disease, diffuse: IV 0.5 to 1.5 mg/kg/dose every day or every other day for several weeks, followed by an oral azole antifungal for a total length of therapy ≥12 months

HIV-exposed/-positive: Disseminated (non-CNS) disease, diffuse pulmonary disease; severely ill:

Infants and Children: IV: 0.5 to 1 mg/kg/dose once daily until clinical improvement; minimum of several weeks of therapy (HHS [OI pediatric 2013])

Adolescents: IV: 0.7 to 1 mg/kg/dose once daily until clinical improvement, then initiate triazole therapy (eg, fluconazole or itraconazole) (HHS [OI adult 2016])

Cryptococcal disease:

CNS disease:

Non-HIV-exposed/-positive: Infant, Children, and Adolescents: IV: 0.7 to 1 mg/kg/dose once daily plus flucytosine; Note: Minimum 2- to 4-week induction, followed by consolidation and chronic suppressive therapy; may increase amphotericin dose to 1.5 mg/kg/day if flucytosine is not tolerated (IDSA [Perfect 2010])

HIV-exposed/-positive:

Infants and Children: IV: 1 mg/kg/dose once daily plus flucytosine or fluconazole; Note: Minimum 2-week induction, followed by consolidation and chronic suppressive therapy; a longer duration of induction therapy may be necessary if CSF is not negative or lack of clinical improvement; may increase amphotericin dose to 1.5 mg/kg/day alone or in combination with fluconazole if flucytosine is not tolerated (HHS [OI pediatric 2013])

Adolescents: IV: 0.7 to 1 mg/kg/dose once daily with or without flucytosine or fluconazole; Note: Minimum 2-week induction, followed by consolidation and chronic suppressive therapy (HHS [OI adult 2016])

Disseminated (non-CNS disease) or severe pulmonary disease: Independent of HIV status: Infants, Children, and Adolescents: IV: 0.7 to 1 mg/kg/dose once daily with or without flucytosine; duration of therapy depends on the site and severity of the infection and clinical response (HHS [OI adult 2016]; HHS [OI pediatric 2013]; IDSA [Perfect 2010])

Histoplasmosis:

Non-HIV-exposed/-positive: Severe disseminated (non-CNS) or pulmonary disease: Infants, Children, and Adolescents: IV: 0.7 to 1 mg/kg/dose once daily; Note: Minimum 1- to 2-week induction, followed by consolidation therapy (IDSA [Wheat 2007])

HIV-exposed/-positive: CNS or severe disseminated disease: Infants and Children: IV: 0.7 to 1 mg/kg/dose once daily, followed by consolidation therapy (HHS [OI pediatric 2013])

Duration of induction:

Severe or moderately severe pulmonary disease: 1 to 2 week minimum

Disseminated or clinical improvement delayed: ≥2 weeks

CNS involvement: 4 to 6 weeks

Leishmaniasis, visceral (HIV-exposed/-positive): Adolescents: IV: 0.5 to 1 mg/kg/dose once daily for a total cumulative dose of 1,500 to 2,000 mg (HHS [OI adult 2016])

Peritonitis (CAPD): Limited data available: Note: Amphotericin B has demonstrated poor peritoneal penetration when given systemically and intraperitoneal administration is associated with abdominal pain and peritoneal irritation; other agents may be preferred (ISPD [Warady 2012]).

Intraperitoneal, dialysate: Infants, Children, and Adolescents: 1 to 4 mg per liter of dialysate has been used in pediatric patients based on case reports and retrospective reviews (Hogg 1982; Kravitz 1986; Raaijmakers 2007; Warady 2000a); lower doses of 0.5 to 3 mg per liter of dialysate has been reported in adults (with or without concomitant systemic amphotericin B therapy); abdominal pain has been associated with doses ≥2 mg per liter of dialysate (Bastani 1986; Johnson 1985).

IV: Infants, Children, and Adolescents: 1 mg/kg/dose once daily (ISPD [Warady 2000b])

Sporotrichosis, severe infection (IDSA [Kauffman 2007]): Children and Adolescents: 0.7 mg/kg/dose once daily; followed by oral itraconazole after a favorable response is seen with amphotericin initial therapy

Reconstitution

IV: Add 10 mL of SWFI (without a bacteriostatic agent) to each vial of amphotericin B. Further dilute with 250 to 500 mL D5W; final concentration should not exceed 0.1 mg/mL (peripheral infusion) or 0.25 mg/mL (central infusion).

Intraventricular: 0.01 to 0.5 mg in 2 mL D5W; use preservative-free preparations only (IDSA [Tunkel 2017])

Irrigation: For bladder irrigation (off-label use), reconstituted solution is further diluted with 1,000 mL SWFI for a final concentration of 50 mcg/mL (Fisher 2011).

Extemporaneously Prepared

Intravitreal/intracameral injection: Add 10 mL SWFI to a 50 mg vial; withdraw 1 mL of solution and further dilute with 4 mL SWFI for a concentration of 1 mg/mL. Remove 1 mL of 1 mg/mL solution and further dilute with 9 mL SWFI to achieve a final concentration of 0.1 mg/mL. A volume of 0.1 mL of the 0.1 mg/mL solution will contain 10 mcg of amphotericin. Withdraw dose into a 1 mL syringe for immediate administration (stability data are not available) (Kaushik 2001).

Kaushik S, Ram J, Brar GS, Jain AK, Chakraborti A, Gupta A. Intracameral amphotericin B: initial experience in severe keratomycosis. Cornea. 2001;20(7):715-719.11588423

Administration

IV: May be infused over 4 to 6 hours. For a patient who experiences chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related reactions, premedicate with the following drugs 30 to 60 minutes prior to drug administration: A nonsteroidal (eg, ibuprofen, choline magnesium trisalicylate) ± diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone. If the patient experiences rigors during the infusion, meperidine may be administered. Bolus infusion of normal saline immediately preceding, or immediately preceding and following amphotericin B may reduce drug-induced nephrotoxicity. Risk of nephrotoxicity increases with amphotericin B doses >1 mg/kg/day. Infusion of admixtures more concentrated than 0.25 mg/mL should be limited to patients absolutely requiring volume contraction. Pre-infusion administration of 500 to 1,000 mL of normal saline appears to reduce the risk of nephrotoxicity during amphotericin B treatment (HHS [OI adult 2016]).

Intraventricular (off-label route): Use preservative-free preparations only. When administered through a ventricular drain, clamp drain for 15 to 60 minutes before opening the drain to allow amphotericin B solution to equilibrate in the CSF (IDSA [Tunkel 2017])

Irrigation (off-label route): A solution for irrigation (final concentration range: 0.05 to 0.25 mg/mL) may be administered via nephrostomy tubes for fungal balls associated with UTI due to candida. A solution for irrigation (final concentration: 0.05 mg/mL solution) may be instilled via bladder irrigation for cystitis (IDSA [Pappas 2016]).

Storage

Store intact vials under refrigeration. Protect from light. Reconstituted vials are stable, protected from light, for 24 hours at room temperature and 1 week when refrigerated. Parenteral admixtures in D5W are stable, protected from light, for 24 hours at room temperature and 2 days under refrigeration. Short-term exposure (<24 hours) to light during IV infusion does not appreciably affect potency.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminoglycosides: Amphotericin B may enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May diminish the therapeutic effect of Amphotericin B. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Cardiac Glycosides: Amphotericin B may enhance the adverse/toxic effect of Cardiac Glycosides. Monitor therapy

Colistimethate: Amphotericin B may enhance the nephrotoxic effect of Colistimethate. Consider therapy modification

Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Amphotericin B. Monitor therapy

Corticosteroids (Systemic): May enhance the hypokalemic effect of Amphotericin B. Monitor therapy

CycloSPORINE (Systemic): Amphotericin B may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dichlorphenamide: Amphotericin B may enhance the hypokalemic effect of Dichlorphenamide. Monitor therapy

Dronabinol: May increase the serum concentration of Amphotericin B. Specifically, dronabinol may displace amphotericin B from its protein-binding sites, leading to an increased concentration of active, unbound drug. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Fexinidazole [INT]: Amphotericin B may enhance the arrhythmogenic effect of Fexinidazole [INT]. Avoid combination

Flucytosine: Amphotericin B may enhance the adverse/toxic effect of Flucytosine. This may be related to the adverse effects of amphotericin B on renal function. Monitor therapy

Foscarnet: May enhance the nephrotoxic effect of Amphotericin B. Avoid combination

Ganciclovir-Valganciclovir: May enhance the nephrotoxic effect of Amphotericin B. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methoxyflurane: May enhance the nephrotoxic effect of Amphotericin B. Avoid combination

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Sodium Stibogluconate: Amphotericin B (Conventional) may enhance the cardiotoxic effect of Sodium Stibogluconate. Specifically, arrhythmia and sudden cardiac death risks may be increased. Consider therapy modification

Adverse Reactions

Systemic:

>10%:

Cardiovascular: Hypotension

Central nervous system: Chills, headache (less frequent with I.T.), malaise, pain (less frequent with I.T.)

Endocrine & metabolic: Hypokalemia, hypomagnesemia

Gastrointestinal: Anorexia, diarrhea, epigastric pain, heartburn, nausea (less frequent with I.T.), stomach cramps, vomiting (less frequent with I.T.)

Hematologic & oncologic: Anemia (normochromic-normocytic)

Local: Pain at injection site (with or without phlebitis or thrombophlebitis [incidence may increase with peripheral infusion of admixtures])

Renal: Renal function abnormality (including azotemia, renal tubular acidosis, nephrocalcinosis [>0.1 mg/ml]), renal insufficiency

Respiratory: Tachypnea

Miscellaneous: Fever

1% to 10%:

Cardiovascular: Flushing, hypertension

Central nervous system: Arachnoiditis, delirium, neuralgia (lumbar; especially with intrathecal therapy), paresthesia (especially with intrathecal therapy)

Genitourinary: Urinary retention

Hematologic & oncologic: Leukocytosis

<1% (Limited to important or life-threatening): Acute hepatic failure, agranulocytosis, anuria, blood coagulation disorder, bone marrow depression, bronchospasm, cardiac arrest, cardiac arrhythmia, cardiac failure, convulsions, diplopia, dyspnea, eosinophilia, exfoliation of skin, hearing loss, hemorrhagic gastroenteritis, hepatitis, hypersensitivity pneumonitis, increased liver enzymes, jaundice, leukoencephalopathy, leukopenia, maculopapular rash, melena, nephrogenic diabetes insipidus, oliguria, peripheral neuropathy, pruritus, pulmonary edema, renal failure, renal tubular acidosis, shock, Stevens-Johnson syndrome, thrombocytopenia, tinnitus, toxic epidermal necrolysis, ventricular fibrillation, vertigo (transient), visual disturbance, wheezing

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis: Has been reported with amphotericin B-containing drugs; facilities for cardiopulmonary resuscitation should be available during administration due to the possibility of anaphylactic reaction. If severe respiratory distress occurs, the infusion should be immediately discontinued; during the initial dosing, the drug should be administered under close clinical observation.
• Infusion reactions: Acute reactions (eg, fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, tachypnea) may occur 1 to 3 hours after starting an intravenous infusion. These reactions are usually more common with the first few doses and generally diminish with subsequent doses. Avoid rapid infusion to prevent hypotension, hypokalemia, arrhythmias, and shock.
• Leukoencephalopathy: Has been reported following administration of amphotericin. Total body irradiation has been reported to be a possible predisposition.
• Nephrotoxicity: May cause nephrotoxicity; usual risk factors include underlying renal disease, concomitant nephrotoxic medications and daily and/or cumulative dosing of amphotericin. Avoid use with other nephrotoxic drugs; drug-induced renal toxicity usually improves with interrupting therapy, decreasing dosage, or increasing dosing interval. However permanent impairment may occur, especially in patients receiving large cumulative dose (eg, >5 g) and in those also receiving other nephrotoxic drugs. Hydration and sodium repletion prior to administration may reduce the risk of developing nephrotoxicity. Frequent monitoring of renal function is recommended.

Disease-related concerns:

• Fungal infections: [US Boxed Warning]: Should be used primarily for treatment of progressive, potentially life-threatening fungal infections, not noninvasive forms of infection.
• Heart failure: In a scientific statement from the American Heart Association, amphotericin has been determined to be an agent that may cause direct myocardial toxicity (magnitude: moderate/major) (AHA [Page 2016]).
• Renal impairment: Use with caution in patients with renal impairment.

Special populations:

• Neutropenic patients: Pulmonary reactions may occur in neutropenic patients receiving leukocyte transfusions; separation of the infusions as much as possible is advised.

Other warnings/precautions:

• Error prevention: [US Boxed warning]: Verify the product name and dosage if dose exceeds 1.5 mg/kg.
• Therapy interruption: If therapy is stopped for >7 days, restart at the lowest dose recommended and increase gradually.

Monitoring Parameters

BUN and serum creatinine levels should be determined every other day when therapy is increased and at least weekly thereafter. Renal function (monitor frequently during therapy), electrolytes (especially potassium and magnesium), liver function tests, temperature, PT/PTT, CBC; monitor input and output; monitor for signs of hypokalemia (muscle weakness, cramping, drowsiness, ECG changes, etc)

Pregnancy

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Amphotericin crosses the placenta and enters the fetal circulation. Amphotericin B is recommended for the treatment of serious systemic fungal diseases in pregnant women. Refer to current guidelines (IDSA [Pappas 2016]; King 1998; Pilmis 2015).

Patient Education

What is this drug used for?

• It is used to treat fungal infections.

Frequently reported side effects of this drug

• Abdominal pain
• Abdominal cramps
• Heartburn
• Diarrhea
• Lack of appetite
• Weight loss
• Muscle pain
• Joint pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• Chills
• Severe dizziness
• Passing out
• Severe nausea
• Vomiting
• Fast breathing
• Severe loss of strength and energy
• Severe headache
• Severe injection site pain, redness, burning, swelling, or irritation
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.